Epilepsy
Conditions
Keywords
Epilepsy, BIA 2-093
Brief summary
The purpose of this study is to characterize the pharmacokinetics of Eslicarbazepine acetate in children and adolescents with epilepsy.
Detailed description
This clinical study was planned to be performed as an open-label, single-centre, multiple-dose study, in 30 paediatric epileptic patients distributed by 3 age groups of 10 patients each: 2-6 years \[Group 1\], 7-11 years \[Group 2\], and 12-17 years \[Group 3\]. The study was constituted by a 4-week baseline phase, followed by 3 consecutive 4-week treatment periods with Eslicarbazepine acetate in which patients received Eslicarbazepine acetate once-daily at the following dosage regimens: 5 mg/kg/day (weeks 1-4), 15 mg/kg/day (weeks 5-8) and 30 mg/kg/day or 1800 mg/day, whichever less (weeks 9-12). At the end of each 4-week treatment period, patients were hospitalised and serial blood samples for drug assays were obtained over a dosing interval. After the last treatment period or in the event of premature discontinuation, the dose had to be down-titrated during a 2-week period. After the last treatment period patient could continue receiving Eslicarbazepine acetate (compassionate use) if both parent(s)/guardian(s) /patient and his/her physician agreed this was in the best patient's interest. A follow-up visit occurred approximately 4 weeks after the last hospitalisation or early discontinuation.
Interventions
DRUGBIA 2-093 (Eslicarbazepine acetate)
Eslicarbazepine acetate administered at increasing daily doses of 5 mg/kg, 15 mg/kg, and 30 mg/kg (or 1800 mg, whichever less); once-daily; oral route
Sponsors
Bial - Portela C S.A.
Study design
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
The following inclusion criteria were applied in selecting patients for participation in the trial. Patient was eligible for entry into the baseline phase if he/she fulfilled the following criteria at Visit 1: * Written informed consent given by the parent(s)/guardian(s), and by the patient when appropriate. * Male or female patient aged between 2 and 17 years. * Body weight within the 10th and 90th percentiles, by age and sex. * A documented diagnosis of partial-onset seizures (simple or complex seizures with or without secondary generalisation), classified according to the International Classification of Epileptic Seizures. * Currently treated with 1 to 3 AEDs (any except OXC or CBZ), in a stable dosage regimen during at least 1 month prior to screening. * Good general health (apart from epilepsy) based on medical history and physical examination. * In case of a female patient, she was premenarchal, surgically sterile or presented a urine pregnancy test consistent with a non-gravid state and practiced an effective non-hormonal contraception method. At Visit 2, patient was eligible for entry into the Eslicarbazepine acetate treatment phase if he/she fulfilled the following criteria: * At least 4 partial-onset seizures during the last 4 weeks of the baseline phase. * Brain CT scan or MRI that excluded rapidly progressive neurological diseases. * ECG without clinically significant abnormalities. * Good general health (apart from epilepsy) based on medical history, physical examination and laboratory tests at screening. * Diaries satisfactorily completed by the patient or his/her caregiver during the baseline phase. * Satisfactory compliance with the study requirements during the baseline phase. * In case of a female patient of childbearing potential, she presented a urine pregnancy test consistent with a non-gravid state and practiced an effective non-hormonal contraception method.
Exclusion criteria
Patient was not allowed for entry into the screening phase if he/she fulfilled the following criteria at Visit 1: * Primarily generalised epilepsy. * Clinically relevant medical condition, other than epilepsy. * History of status epilepticus in the last 3 months. * History of suicide attempt. * History of alcohol or drug abuse. * History of hypersensitivity or intolerance to OXC or CBZ. * Use of any investigational drug or participated in any clinical trial within the previous 2 months. * Patient and/or his/her caregiver(s) unlikely to co-operate with the requirements of the study. * If female, she was sexually active and of child-bearing potential and she did not use reliable contraception. * Patients with non-epileptic attacks (syncopes, pseudoseizures). * Previous poor compliance with anti-epileptic therapy. * Need for rescue benzodiazepines more frequently than twice per week on average. * Previous use of Eslicarbazepine acetate or participation in a clinical study with Eslicarbazepine acetate. * Any other condition or circumstance that, in the opinion of the investigator, might compromise the patient's ability to comply with the clinical trial protocol (CTP). At Visit 2, patient was not eligible for entry into the Eslicarbazepine acetate treatment phase if he/she fulfilled the following criteria: * Inadequate compliance to concomitant AEDs during the baseline phase. * Clinically relevant clinical laboratory test abnormalities at screening. * Occurrence of any other condition or circumstance that, in the opinion of the investigator, might compromise the patient's ability to comply with the CTP.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Time of Occurrence of Cmax (Tmax). | pre-dose, and ½, 1½, 3, 4½, 6 and 12 hours post-dose |
| Maximum Observed Plasma Drug Concentration (Cmax) Post-dose | pre-dose, and ½, 1½, 3, 4½, 6 and 12 hours post-dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Seizure Frequency During Each 4-week Treatment Period Compared to the Baseline Phase | Baseline, end of 5 mg/kg/day treatment period (4 weeks), 15 mg/kg/day treatment period (4 weeks) and 30 mg/kg/day treatment period (4 weeks). | The efficacy variables were the percentage change in seizure frequency during each 4-week treatment period compared to the baseline phase. Seizures were recorded in the patient's diary during the baseline phase and during the following 4-week treatment periods. Seizure frequency for each patient was standardised to a frequency per 28 days period (i.e., mean daily frequency multiplied by 28). Changes in seizure frequency were analysed for each age group separately. |
Countries
Romania
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1 (2-6 Yrs) Efficacy population (EP) | 11 |
| Group 2 (7-11 Yrs) Efficacy population (EP) | 8 |
| Group 3 (12-17 Yrs) Efficacy population (EP) | 10 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 1 | 1 |
Baseline characteristics
| Characteristic | Group 1 (2-6 Yrs) | Group 2 (7-11 Yrs) | Group 3 (12-17 Yrs) | Total |
|---|---|---|---|---|
| Age, Continuous | 4.1 years STANDARD_DEVIATION 1.38 | 9.1 years STANDARD_DEVIATION 1.55 | 14.5 years STANDARD_DEVIATION 1.58 | 9.1 years STANDARD_DEVIATION 4.73 |
| Sex: Female, Male Female | 8 Participants | 6 Participants | 3 Participants | 17 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 7 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 12 | 7 / 8 | 7 / 11 |
| serious Total, serious adverse events | 2 / 12 | 1 / 8 | 0 / 11 |
Outcome results
Primary
Maximum Observed Plasma Drug Concentration (Cmax) Post-dose
Time frame: pre-dose, and ½, 1½, 3, 4½, 6 and 12 hours post-dose
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 (2-6 Yrs) | Maximum Observed Plasma Drug Concentration (Cmax) Post-dose | Dosage regimen 15 mg/kg/day | 16183 ng/mL | Standard Deviation 2609 |
| Group 1 (2-6 Yrs) | Maximum Observed Plasma Drug Concentration (Cmax) Post-dose | Dosage regimen 5 mg/kg/day | 6921 ng/mL | Standard Deviation 1794 |
| Group 1 (2-6 Yrs) | Maximum Observed Plasma Drug Concentration (Cmax) Post-dose | Dosage regimen 30 mg/kg/day | 29935 ng/mL | Standard Deviation 4627 |
| Group 2 (7-11 Yrs) | Maximum Observed Plasma Drug Concentration (Cmax) Post-dose | Dosage regimen 15 mg/kg/day | 16395 ng/mL | Standard Deviation 3680 |
| Group 2 (7-11 Yrs) | Maximum Observed Plasma Drug Concentration (Cmax) Post-dose | Dosage regimen 5 mg/kg/day | 4820 ng/mL | Standard Deviation 1693 |
| Group 2 (7-11 Yrs) | Maximum Observed Plasma Drug Concentration (Cmax) Post-dose | Dosage regimen 30 mg/kg/day | 26890 ng/mL | Standard Deviation 6944 |
| Group 3 (12-17 Yrs) | Maximum Observed Plasma Drug Concentration (Cmax) Post-dose | Dosage regimen 5 mg/kg/day | 6382 ng/mL | Standard Deviation 1854 |
| Group 3 (12-17 Yrs) | Maximum Observed Plasma Drug Concentration (Cmax) Post-dose | Dosage regimen 30 mg/kg/day | 32400 ng/mL | Standard Deviation 6005 |
| Group 3 (12-17 Yrs) | Maximum Observed Plasma Drug Concentration (Cmax) Post-dose | Dosage regimen 15 mg/kg/day | 17194 ng/mL | Standard Deviation 3410 |
Primary
Time of Occurrence of Cmax (Tmax).
Time frame: pre-dose, and ½, 1½, 3, 4½, 6 and 12 hours post-dose
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 (2-6 Yrs) | Time of Occurrence of Cmax (Tmax). | Dosage regimen 30 mg/kg/day | 1 hours | Standard Deviation 0 |
| Group 1 (2-6 Yrs) | Time of Occurrence of Cmax (Tmax). | Dosage regimen 5 mg/kg/day | 1 hours | Standard Deviation 1 |
| Group 1 (2-6 Yrs) | Time of Occurrence of Cmax (Tmax). | Dosage regimen 15 mg/kg/day | 2 hours | Standard Deviation 1 |
| Group 2 (7-11 Yrs) | Time of Occurrence of Cmax (Tmax). | Dosage regimen 30 mg/kg/day | 3 hours | Standard Deviation 1 |
| Group 2 (7-11 Yrs) | Time of Occurrence of Cmax (Tmax). | Dosage regimen 15 mg/kg/day | 3 hours | Standard Deviation 1 |
| Group 2 (7-11 Yrs) | Time of Occurrence of Cmax (Tmax). | Dosage regimen 5 mg/kg/day | 2 hours | Standard Deviation 1 |
| Group 3 (12-17 Yrs) | Time of Occurrence of Cmax (Tmax). | Dosage regimen 30 mg/kg/day | 3 hours | Standard Deviation 2 |
| Group 3 (12-17 Yrs) | Time of Occurrence of Cmax (Tmax). | Dosage regimen 15 mg/kg/day | 2 hours | Standard Deviation 1 |
| Group 3 (12-17 Yrs) | Time of Occurrence of Cmax (Tmax). | Dosage regimen 5 mg/kg/day | 2 hours | Standard Deviation 1 |
Secondary
Percentage Change in Seizure Frequency During Each 4-week Treatment Period Compared to the Baseline Phase
The efficacy variables were the percentage change in seizure frequency during each 4-week treatment period compared to the baseline phase. Seizures were recorded in the patient's diary during the baseline phase and during the following 4-week treatment periods. Seizure frequency for each patient was standardised to a frequency per 28 days period (i.e., mean daily frequency multiplied by 28). Changes in seizure frequency were analysed for each age group separately.
Time frame: Baseline, end of 5 mg/kg/day treatment period (4 weeks), 15 mg/kg/day treatment period (4 weeks) and 30 mg/kg/day treatment period (4 weeks).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group 1 (2-6 Yrs) | Percentage Change in Seizure Frequency During Each 4-week Treatment Period Compared to the Baseline Phase | Dosage regimen 15 mg/kg/day | -24.8 percent change |
| Group 1 (2-6 Yrs) | Percentage Change in Seizure Frequency During Each 4-week Treatment Period Compared to the Baseline Phase | 5Dosage regimen 5 mg/kg/day | -28.2 percent change |
| Group 1 (2-6 Yrs) | Percentage Change in Seizure Frequency During Each 4-week Treatment Period Compared to the Baseline Phase | Dosage regimen 30 mg/kg/day | -40.6 percent change |
| Group 2 (7-11 Yrs) | Percentage Change in Seizure Frequency During Each 4-week Treatment Period Compared to the Baseline Phase | Dosage regimen 15 mg/kg/day | 5.0 percent change |
| Group 2 (7-11 Yrs) | Percentage Change in Seizure Frequency During Each 4-week Treatment Period Compared to the Baseline Phase | 5Dosage regimen 5 mg/kg/day | -11.7 percent change |
| Group 2 (7-11 Yrs) | Percentage Change in Seizure Frequency During Each 4-week Treatment Period Compared to the Baseline Phase | Dosage regimen 30 mg/kg/day | 12.2 percent change |
| Group 3 (12-17 Yrs) | Percentage Change in Seizure Frequency During Each 4-week Treatment Period Compared to the Baseline Phase | 5Dosage regimen 5 mg/kg/day | -17.1 percent change |
| Group 3 (12-17 Yrs) | Percentage Change in Seizure Frequency During Each 4-week Treatment Period Compared to the Baseline Phase | Dosage regimen 30 mg/kg/day | -43.1 percent change |
| Group 3 (12-17 Yrs) | Percentage Change in Seizure Frequency During Each 4-week Treatment Period Compared to the Baseline Phase | Dosage regimen 15 mg/kg/day | -31.7 percent change |